tbuckley/cabot-search huggingface dataset:
Innate Immunity System in Patients With Cardiovascular and Kidney Disease
Authors: Carmine Zoccali, Francesca Mallamaci
Journal: Circulation Research (2023)

With a global burden of 844 million, chronic kidney disease (CKD) is now considered a public health priority. Cardiovascular risk is pervasive in this population, and low-grade systemic inflammation is an established driver of adverse cardiovascular outcomes in these patients. Accelerated cellular senescence, gut microbiota-dependent immune activation, posttranslational lipoprotein modifications, neuroimmune interactions, osmotic and nonosmotic sodium accumulation, acute kidney injury, and precipitation of crystals in the kidney and the vascular system all concur in determining the unique severity of inflammation in CKD. Cohort studies documented a strong link between various biomarkers of inflammation and the risk of progression to kidney failure and cardiovascular events in patients with CKD. Interventions targeting diverse steps of the innate immune response may reduce the risk of cardiovascular and kidney disease. Among these, inhibition of IL-1β (interleukin-1 beta) signaling by canakinumab reduced the risk for cardiovascular events in patients with coronary heart disease, and this protection was equally strong in patients with and without CKD. Several old (colchicine) and new drugs targeting the innate immune system, like the IL-6 (interleukin 6) antagonist ziltivekimab, are being tested in large randomized clinical trials to thoroughly test the hypothesis that mitigating inflammation may translate into better cardiovascular and kidney outcomes in patients with CKD.
An immunogenic and oncogenic feature-based classification for chemotherapy plus PD-1 blockade in advanced esophageal squamous cell carcinoma
Authors: Yan-Xing Chen, Zi-Xian Wang, Ying Jin, Qi Zhao, Ze-Xian Liu, Zhi-Xiang Zuo, Huai-Qiang Ju, Chengxu Cui, Jun Yao, Yanqiao Zhang, Mengxia Li, Jifeng Feng, Lin Tian, Xiao-Jun Xia, Hui Feng, Sheng Yao, Feng-Hua Wang, Yu-Hong Li, Feng Wang, Rui-Hua Xu
Journal: Cancer Cell (2023)
Endothelial Cell Dysfunction and Increased Cardiovascular Risk in Patients With Chronic Kidney Disease
Authors: Constance C.F.M.J. Baaten, Sonja Vondenhoff, Heidi Noels
Journal: Circulation Research (2023)

The endothelium is considered to be the gatekeeper of the vessel wall, maintaining and regulating vascular integrity. In patients with chronic kidney disease, protective endothelial cell functions are impaired due to the proinflammatory, prothrombotic and uremic environment caused by the decline in kidney function, adding to the increase in cardiovascular complications in this vulnerable patient population. In this review, we discuss endothelial cell functioning in healthy conditions and the contribution of endothelial cell dysfunction to cardiovascular disease. Further, we summarize the phenotypic changes of the endothelium in chronic kidney disease patients and the relation of endothelial cell dysfunction to cardiovascular risk in chronic kidney disease. We also review the mechanisms that underlie endothelial changes in chronic kidney disease and consider potential pharmacological interventions that can ameliorate endothelial health.
Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma
Authors: Giorgio Gaglia, Megan L Burger, Cecily C Ritch, Danae Rammos, Yang Dai, Grace E Crossland, Sara Z Tavana, Simon Warchol, Alex M Jaeger, Santiago Naranjo, Shannon Coy, Ajit J Nirmal, Robert Krueger, Jia-Ren Lin, Hanspeter Pfister, Peter K Sorger, Tyler Jacks, Sandro Santagata
Journal: Cancer Cell (2023)
Role of the Microbiome in Gut-Heart-Kidney Cross Talk
Authors: Griet Glorieux, Sanjay K. Nigam, Raymond Vanholder, Francis Verbeke
Journal: Circulation Research (2023)

Homeostasis is a prerequisite for health. When homeostasis becomes disrupted, dysfunction occurs. This is especially the case for the gut microbiota, which under normal conditions lives in symbiosis with the host. As there are as many microbial cells in and on our body as human cells, it is unlikely they would not contribute to health or disease. The gut bacterial metabolism generates numerous beneficial metabolites but also uremic toxins and their precursors, which are transported into the circulation. Barrier function in the intestine, the heart, and the kidneys regulates metabolite transport and concentration and plays a role in inter-organ and inter-organism communication via small molecules. This communication is analyzed from the perspective of the remote sensing and signaling theory, which emphasizes the role of a large network of multispecific, oligospecific, and monospecific transporters and enzymes in regulating small-molecule homeostasis. The theory provides a systems biology framework for understanding organ cross talk and microbe-host communication involving metabolites, signaling molecules, nutrients, antioxidants, and uremic toxins. This remote small-molecule communication is critical for maintenance of homeostasis along the gut-heart-kidney axis and for responding to homeostatic perturbations. Chronic kidney disease is characterized by gut dysbiosis and accumulation of toxic metabolites. This slowly impacts the body, affecting the cardiovascular system and contributing to the progression of kidney dysfunction, which in its turn influences the gut microbiota. Preserving gut homeostasis and barrier functions or restoring gut dysbiosis and dysfunction could be a minimally invasive way to improve patient outcomes and quality of life in many diseases, including cardiovascular and kidney disease.
Use of Computation Ecosystems to Analyze the Kidney-Heart Crosstalk
Authors: Zhuojun Wu, Johannes Lohmöller, Christiane Kuhl, Klaus Wehrle, Joachim Jankowski
Journal: Circulation Research (2023)

The identification of mediators for physiologic processes, correlation of molecular processes, or even pathophysiological processes within a single organ such as the kidney or heart has been extensively studied to answer specific research questions using organ-centered approaches in the past 50 years. However, it has become evident that these approaches do not adequately complement each other and display a distorted single-disease progression, lacking holistic multilevel/multidimensional correlations. Holistic approaches have become increasingly significant in understanding and uncovering high dimensional interactions and molecular overlaps between different organ systems in the pathophysiology of multimorbid and systemic diseases like cardiorenal syndrome because of pathological heart-kidney crosstalk. Holistic approaches to unraveling multimorbid diseases are based on the integration, merging, and correlation of extensive, heterogeneous, and multidimensional data from different data sources, both -omics and nonomics databases. These approaches aimed at generating viable and translatable disease models using mathematical, statistical, and computational tools, thereby creating first computational ecosystems. As part of these computational ecosystems, systems medicine solutions focus on the analysis of -omics data in single-organ diseases. However, the data-scientific requirements to address the complexity of multimodality and multimorbidity reach far beyond what is currently available and require multiphased and cross-sectional approaches. These approaches break down complexity into small and comprehensible challenges. Such holistic computational ecosystems encompass data, methods, processes, and interdisciplinary knowledge to manage the complexity of multiorgan crosstalk. Therefore, this review summarizes the current knowledge of kidney-heart crosstalk, along with methods and opportunities that arise from the novel application of computational ecosystems providing a holistic analysis on the example of kidney-heart crosstalk.
Cardiac Metabolism in Heart Failure and Implications for Uremic Cardiomyopathy
Authors: T. Dung Nguyen, P. Christian Schulze
Journal: Circulation Research (2023)

Chronic kidney disease is associated with an increased risk for the development and progression of cardiovascular disorders including hypertension, dyslipidemia, and coronary artery disease. Chronic kidney disease may also affect the myocardium through complex systemic changes, resulting in structural remodeling such as hypertrophy and fibrosis, as well as impairments in both diastolic and systolic function. These cardiac changes in the setting of chronic kidney disease define a specific cardiomyopathic phenotype known as uremic cardiomyopathy. Cardiac function is tightly linked to its metabolism, and research over the past 3 decades has revealed significant metabolic remodeling in the myocardium during the development of heart failure. Because the concept of uremic cardiomyopathy has only been recognized in recent years, there are limited data on metabolism in the uremic heart. Nonetheless, recent findings suggest overlapping mechanisms with heart failure. This work reviews key features of metabolic remodeling in the failing heart in the general population and extends this to patients with chronic kidney disease. The knowledge of similarities and differences in cardiac metabolism between heart failure and uremic cardiomyopathy may help identify new targets for mechanistic and therapeutic research on uremic cardiomyopathy.
Hypertension as Cardiovascular Risk Factor in Chronic Kidney Disease
Authors: Michel Burnier, Aikaterini Damianaki
Journal: Circulation Research (2023)

Hypertension is the leading modifiable cause of premature death and hence one of the global targets of World Health Organization for prevention. Hypertension also affects the great majority of patients with chronic kidney disease (CKD). Both hypertension and CKD are intrinsically related, as hypertension is a strong determinant of worse renal and cardiovascular outcomes and renal function decline aggravates hypertension. This bidirectional relationship is well documented by the high prevalence of hypertension across CKD stages and the dual benefits of effective antihypertensive treatments on renal and cardiovascular risk reduction. Achieving an optimal blood pressure (BP) target is mandatory and requires several pharmacological and lifestyle measures. However, it also requires a correct diagnosis based on reliable BP measurements (eg, 24-hour ambulatory BP monitoring, home BP), especially for populations like patients with CKD where reduced or reverse dipping patterns or masked and resistant hypertension are frequent and associated with a poor cardiovascular and renal prognosis. Even after achieving BP targets, which remain debated in CKD, the residual cardiovascular risk remains high. Current antihypertensive options have been enriched with novel agents that enable to lower the existing renal and cardiovascular risks, such as SGLT2 (sodium-glucose cotransporter-2) inhibitors and novel nonsteroidal mineralocorticoid receptor antagonists. Although their beneficial effects may be driven mostly from actions beyond BP control, recent evidence underline potential improvements on abnormal 24-hour BP phenotypes such as nondipping. Other promising novelties are still to come for the management of hypertension in CKD. In the present review, we shall discuss the existing evidence of hypertension as a cardiovascular risk factor in CKD, the importance of identifying hypertension phenotypes among patients with CKD, and the traditional and novel aspects of the management of hypertensives with CKD.
Cardiovascular Calcification Heterogeneity in Chronic Kidney Disease
Authors: Joshua D. Hutcheson, Claudia Goettsch
Journal: Circulation Research (2023)

Patients with chronic kidney disease (CKD) exhibit tremendously elevated risk for cardiovascular disease, particularly ischemic heart disease, due to premature vascular and cardiac aging and accelerated ectopic calcification. The presence of cardiovascular calcification associates with increased risk in patients with CKD. Disturbed mineral homeostasis and diverse comorbidities in these patients drive increased systemic cardiovascular calcification in different manifestations with diverse clinical consequences, like plaque instability, vessel stiffening, and aortic stenosis. This review outlines the heterogeneity in calcification patterning, including mineral type and location and potential implications on clinical outcomes. The advent of therapeutics currently in clinical trials may reduce CKD-associated morbidity. Development of therapeutics for cardiovascular calcification begins with the premise that less mineral is better. While restoring diseased tissues to a noncalcified homeostasis remains the ultimate goal, in some cases, calcific mineral may play a protective role, such as in atherosclerotic plaques. Therefore, developing treatments for ectopic calcification may require a nuanced approach that considers individual patient risk factors. Here, we discuss the most common cardiac and vascular calcification pathologies observed in CKD, how mineral in these tissues affects function, and the potential outcomes and considerations for therapeutic strategies that seek to disrupt the nucleation and growth of mineral. Finally, we discuss future patient-specific considerations for treating cardiac and vascular calcification in patients with CKD-a population in need of anticalcification therapies.
Targeted protein degrader development for cancer: advances, challenges, and opportunities
Authors: Yuan Fang, Shuhang Wang, Songzhe Han, Yizhou Zhao, Cunjing Yu, Huaqing Liu, Ning Li
Journal: Trends in Pharmacological Sciences (2023)

Anticancer-targeted therapies inhibit various kinases implicated in cancer and have been used in clinical settings for decades. However, many cancer-related targets are proteins without catalytic activity and are difficult to target using traditional occupancy-driven inhibitors. Targeted protein degradation (TPD) is an emerging therapeutic modality that has expanded the druggable proteome for cancer treatment. With the entry of new-generation immunomodulatory drugs (IMiDs), selective estrogen receptor degraders (SERDs), and proteolysis-targeting chimera (PROTAC) drugs into clinical trials, the field of TPD has seen explosive growth in the past 10 years. Several challenges remain that need to be tackled to increase successful clinical translation of TPD drugs. We present an overview of the global landscape of clinical trials of TPD drugs over the past decade and summarize the clinical profiles of new-generation TPD drugs. In addition, we highlight the challenges and opportunities for the development of effective TPD drugs for future successful clinical translation.
Acute in-competition medical care at the Tokyo 2020 Olympics: a retrospective analysis
Authors: Hideharu Tanaka, Shota Tanaka, Hiroyuki Yokota, Yasuhiro Otomo, Tomohiko Masuno, Kousuke Nakano, Manabu Sugita, Takahiko Tokunaga, Katsuhiko Sugimoto, Junichi Inoue, Nagisa Kato, Tomoya Kinoshi, Syuji Sakanashi, Hironori Inoue, Hiroto Numata, Koshi Nakagawa, Tetsuya Miyamoto, Takao Akama
Journal: British Journal of Sports Medicine (2023)

To analyse injuries and illnesses during the 2020 Tokyo Olympic Summer Games.This retrospective descriptive study included 11 420 athletes from 206 National Olympic Committees and 312 883 non-athletes. Incidences of injuries and illnesses during the competition period from 21 July to 8 August 2021 were analysed.A total of 567 athletes (416 injuries, 51 non-heat-related illnesses and 100 heat-related illnesses) and 541 non-athletes (255 injuries, 161 non-heat-related illnesses and 125 heat-related illnesses) were treated at the competition venue clinic. Patient presentation and hospital transportation rates per 1000 athletes were 50 and 5.8, respectively. Marathons and race walking had the highest incidence of injury and illness overall (17.9%; n=66). The highest incidence of injury (per participant) was noted in boxing (13.8%; n=40), sport climbing (12.5%; n=5) and skateboarding (11.3%; n=9), excluding golf, with the highest incidence of minor injuries. Fewer infectious illnesses than previous Summer Olympics were reported among the participants. Of the 100 heat-related illnesses in athletes, 50 occurred in the marathon and race walking events. Only six individuals were transported to a hospital due to heat-related illness, and none required hospital admission.Injuries and heat-related illnesses were lower than expected at the 2020 Tokyo Olympic Summer Games. No catastrophic events occurred. Appropriate preparation including illness prevention protocols, and treatment and transport decisions at each venue by participating medical personnel may have contributed to these positive results.
Rheumatoid factor autoantibody repertoire profiling reveals distinct binding epitopes in health and autoimmunity
Authors: Nienke Oskam, Pleuni Ooijevaar-De Heer, Dorien Kos, Jorn Jeremiasse, Laurette van Boheemen, Gwenny M Verstappen, Frans G M Kroese, Dirkjan van Schaardenburg, Gertjan Wolbink, Theo Rispens
Journal: Annals of the Rheumatic Diseases (2023)

Rheumatoid factors (RF) are one of the hallmark autoantibodies characteristic of rheumatoid arthritis (RA), and are frequently observed in other diseases and in healthy individuals. RFs comprise multiple subtypes with different specificities towards the constant region of human IgG. Studies indicate that these patterns differ between naturally occurring RFs and RFs associated with disease. However, individual specificities characteristic of either have not been clearly defined.In this study, we developed an extended set of engineered IgG-fragment crystallisable (Fc) targets with preferential RF binding to specific (conformational) epitopes, which was subsequently used for profiling of RF binding patterns in a compiled exploration cohort, consisting of sera from healthy donors with measurable RF and patients with RA, primary Sjögren's syndrome (pSS) and seropositive arthralgia.We identified an epitope that is strongly associated with RA, which was targeted by both IgM-RF and IgA-RF. We also identified an epitope that is preferentially targeted by healthy donor (IgM) RFs. IgM-RFs derived from healthy donors and patients with RA and pSS all target distinct regions on the IgG-Fc, whereas overall, the IgA-RF repertoire is largely restricted to pathology-associated specificities. Using monoclonal RFs with different specificities, we furthermore demonstrate that the capacity to activate complement or even inhibit IgG-mediated complement activation varies according to the epitopes to which RFs bind.Our results demonstrate both the need and feasibility to redefine 'RF' into pathological and physiological autoantibody subtypes.
The anorectic and thermogenic effects of pharmacological lactate in male mice are confounded by treatment osmolarity and co-administered counterions
Authors: Jens Lund, Alberte Wollesen Breum, Cláudia Gil, Sarah Falk, Frederike Sass, Marie Sophie Isidor, Oksana Dmytriyeva, Pablo Ranea-Robles, Cecilie Vad Mathiesen, Astrid Linde Basse, Olivia Sveidahl Johansen, Nicole Fadahunsi, Camilla Lund, Trine Sand Nicolaisen, Anders Bue Klein, Tao Ma, Brice Emanuelli, Maximilian Kleinert, Charlotte Mehlin Sørensen, Zachary Gerhart-Hines, Christoffer Clemmensen
Journal: Nature Metabolism (2023)
Novel strategies for cancer immunotherapy: counter-immunoediting therapy
Authors: Shaochuan Liu, Qian Sun, Xiubao Ren
Journal: Journal of Hematology & Oncology (2023)

Abstract The advent of immunotherapy has made an indelible mark on the field of cancer therapy, especially the application of immune checkpoint inhibitors in clinical practice. Although immunotherapy has proven its efficacy and safety in some tumors, many patients still have innate or acquired resistance to immunotherapy. The emergence of this phenomenon is closely related to the highly heterogeneous immune microenvironment formed by tumor cells after undergoing cancer immunoediting. The process of cancer immunoediting refers to the cooperative interaction between tumor cells and the immune system that involves three phases: elimination, equilibrium, and escape. During these phases, conflicting interactions between the immune system and tumor cells result in the formation of a complex immune microenvironment, which contributes to the acquisition of different levels of immunotherapy resistance in tumor cells. In this review, we summarize the characteristics of different phases of cancer immunoediting and the corresponding therapeutic tools, and we propose normalized therapeutic strategies based on immunophenotyping. The process of cancer immunoediting is retrograded through targeted interventions in different phases of cancer immunoediting, making immunotherapy in the context of precision therapy the most promising therapy to cure cancer.
Re: Mark N. Brook, Holly Ní Raghallaigh, Koveela Govindasami, et al. Family History of Prostate Cancer and Survival Outcomes in the UK Genetic Prostate Cancer Study. Eur Urol 2023;83:257–66
Authors: Kari Hemminki, Jianguang Ji, Jan Sundquist
Journal: European Urology (2023)
Actionable Solutions to Achieve Health Equity in Chronic Liver Disease
Authors: Patricia D. Jones, Jennifer C. Lai, Jasmohan S. Bajaj, Fasiha Kanwal
Journal: Clinical Gastroenterology and Hepatology (2023)

There are well-described racial and ethnic disparities in the burden of chronic liver diseases. Hispanic persons are at highest risk for developing nonalcoholic fatty liver disease, the fastest growing cause of liver disease. Hepatitis B disproportionately affects persons of Asian or African descent. The highest rates of hepatitis C occur in American Indian and Alaskan Native populations. In addition to disparities in disease burden, there are also marked racial and ethnic disparities in access to treatments, including liver transplantation. Disparities also exist by gender and geography, especially in alcohol-related liver disease. To achieve health equity, we must address the root causes that drive these inequities. Understanding the role that social determinants of health play in the disparate health outcomes that are currently observed is critically important. We must forge and/or strengthen collaborations between patients, community members, other key stakeholders, health care providers, health care institutions, professional societies, and legislative bodies. Herein, we provide a high-level review of current disparities in chronic liver disease and describe actionable strategies that have potential to bridge gaps, improve quality, and promote equity in liver care.
Comparative effectiveness of 5-aminolevulinic acid photodynamic therapy with no incubation versus one-hour incubation for the treatment of actinic keratosis: A randomized controlled trial
Authors: Noor Anvery, Rachel E. Christensen, McKenzie A. Dirr, Michael D. Yi, Tyler Johnson, Alexandra Weil, Rachel Kyllo, Sabina Raja, Matthew Rapcan, Joaquin C. Brieva, Simon S. Yoo, Emily Poon, Murad Alam
Journal: Journal of the American Academy of Dermatology (2023)